Psychiatric and neurologic disorders are among the most severe and chronic diseases and conditions. These disorders are also extremely difficult to treat effectively because of the multiplicity of the symptoms and etiologies.
Amongst the therapeutic arsenal to combat these psychiatric and neurologic disorders, sigma receptor inhibitors have been found useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J. M. et al, Pharmacological Reviews, 1990, 42, 355).
WO2006021462 and WO2007098953 describe pyrazole-containing compounds having pharmacological activity towards the sigma receptor, being particularly useful in the therapy of pain, in particular neuropathic pain or allodynia. These compounds have the following chemical structure:

These compounds may be prepared according to the route schemes disclosed in WO2006021462 and WO2007098953. Of particular interest are the intermediates represented by the formula (II) in said patent applications:
wherein R3 and R4, together with the phenyl ring to which they are attached form a naphthyl ring.
According to the routes presented in the mentioned patent applications, these intermediates can be prepared by reacting a acetohydrazide derivative with an ethyl acetoacetate; by reacting an hydrazine derivative with an ethyl butynoate; or by the method provided by F. Effenberger and W. Hartmann, Chem. Ber., 102(10), 3260-3267, 1969, where an ethoxy-acrylic acid hydrazide is reacted with concentrated mineral acid.
C. Venturello and R. D'Aloisio, Synthesis 1979, describes a process to synthesize 2-arylazo-2,5-dimethyl-3-oxo-2,3-dihydrofurans, which are useful intermediates in the synthesis of 1-aryl-5-methyl-3-pyrazolones. In said process, 1-aryl-5-methyl-3-oxo-2,3-dihydropyrazoles (5) are prepared according to method A by adding to concentrated hydrochloric acid while is taken care that the temperature of the mixture does not exceed 30° C. In Method B, 2-arylazo-2,5-dimethyl-3-oxo-2,3-dihydrofuran (3) is dissolved in an acetic/concentrated hydrochloric acid mixture (12.5:1 v/v; 10 ml), keeping the solution at 25-50° C.
In the methods provided by Venturello et al., the exemplified aryl derivatives are all restricted to phenyl-containing compounds. Phenyl and naphthyl rings have distinct reactivity due to a difference in the n-stabilization energy of the aromatic rings. In addition, the naphthyl radical introduces a bigger steric hindrance that the phenyl radical. Moreover, these methods are devised for a laboratory environment, and have not been validated for a scalable process.
During pharmaceutical development, optimized processes to synthesize molecules such as intermediates or final products are sought. Increased yields, purity, simplification of the routes, and the provision of up-scalable processes are amongst the objectives for the chemical developers. Often, chemists are challenged with finding that specific balance between an up-scalable process and a sufficient purity or yield. The use of not too extreme conditions during the process, as well as the use of non-toxic reagents, is part of the equation that the chemist needs to solve.
Hence, an objective of the present invention is to provide a process for the preparation of naphthalen-2-yl-pyrazol-3-one intermediates, which process can improve at least one or more of the following process related parameters, i.e. purity, yield, simplification of the synthetic route, use of affordable conditions, use of environmental-friendly conditions, use of non-toxic reagents, or improved processability of the reagents or final intermediate products.